Irreversible binding of a novel phenylisothiocyanate tropane analog to monoamine transporters in rat brain.

  title={Irreversible binding of a novel phenylisothiocyanate tropane analog to monoamine transporters in rat brain.},
  author={V. Murthy and Huw M. L. Davies and Simon J. Hedley and Steven R. Childers},
  journal={Biochemical pharmacology},
  volume={74 2},
Irreversible tropane analogs have been useful in identifying binding sites of cocaine on biogenic amine transporters, including transporters for dopamine (DAT), serotonin (SERT) and norepinephrine (NET). The present study characterizes the properties of the novel phenylisothiocyanate tropane HD-205, synthesized from the highly potent 2-napthyl tropane analog WF-23. In radioligand binding studies in brain membranes, direct IC(50) values of HD-205 were 4.1, 14 and 280nM at DAT, SERT and NET… Expand
In Vivo Characterization of a Novel Phenylisothiocyanate Tropane Analog at Monoamine Transporters in Rat Brain
The irreversible effects of HD-205 in vivo in rats after intracranial injection was evaluated to evaluate the neuroanatomical basis of DAT-mediated cocaine effects and a strategy of site-specific chemical blockade of transporters was proposed. Expand
A novel photoaffinity ligand for the dopamine transporter based on pyrovalerone.
A ligand was synthesized in which the aromatic ring of pyrovalerone was substituted with a photoreactive azido group, demonstrating appreciable binding affinity for the dopamine transporter and suggesting the potential utility of a radioiodinated version in structure-function studies of this protein. Expand
Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta): Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling.
Compound (±)-3a represents the first successful example of a DAT photoaffinity ligand based on the methylphenidate scaffold and is expected to assist in mapping non-tropane ligand-binding pockets within plasma membrane monoamine transporters. Expand


Novel 2-substituted cocaine analogs: uptake and ligand binding studies at dopamine, serotonin and norepinephrine transport sites in the rat brain.
The results suggest that large variations in the tropane structure do not result in a differentiation between binding at biogenic amine transporters and inhibition of amine uptake. Expand
Dual incorporation of photoaffinity ligands on dopamine transporters implicates proximity of labeled domains.
Results suggest that the two domains may be in close three-dimensional proximity and contribute to binding of multiple uptake blockers and reflect antagonist-induced conformational changes in the loop related to transport inhibition. Expand
Novel tropane-based irreversible ligands for the dopamine transporter.
Evaluation of these compounds for displacing [3H]WIN 35 428 binding at DAT in rat caudate putamen revealed that the 4'-azido-3'-iodophenylbutyl substituent provided optimal binding affinity and was chosen to replace the N-CH3 group on 2. Expand
Differential Binding of Tropane-Based Photoaffinity Ligands on the Dopamine Transporter
The results support previously derived structure–activity relationships suggesting that benztropine and cocaine analogs bind to different domains on the dopamine transporter and indicate promise for the development of benz Tropine-based molecules for cocaine substitution therapies. Expand
Pharmacological profile of radioligand binding to the norepinephrine transporter: instances of poor indication of functional activity
The results indicate that the standard [3H]nisoxetine binding assay at 0 degrees C with cell membrane preparations in high Na+ buffer underestimates the functional potency of compounds related to cocaine and GBR 12909. Expand
Studies of the biogenic amine transporters. IV. Demonstration of a multiplicity of binding sites in rat caudate membranes for the cocaine analog [125I]RTI-55.
Evidence is provided that [125I]RTI-55 labels multiple binding sites associated with the DA and 5-HT transporters, strongly supporting the idea that site 2 is a binding site on the serotonin (5-HT) transporter. Expand
Novel 2-substituted cocaine analogs: binding properties at dopamine transport sites in rat striatum.
A novel scheme utilizing vinylcarbenoid precursors has been developed for the synthesis of novel tropane analogs of cocaine, and the most potent analog was a 2-naphthyl derivative. Expand
Synthesis and preliminary characterization of a high‐affinity novel radioligand for the dopamine transporter
The pharmacological profile of [3H]O‐972 indicated that DAT inhibitors, which include GBR 12909, mazindol, CFT, and cocaine, could potently displace this novel radioligand from monkey brain striatum tissue. Expand
Localization of Cocaine Analog [125I]RTI 82 Irreversible Binding to Transmembrane Domain 6 of the Dopamine Transporter*
Positive evidence is provided for the proximity of cocaine binding to TM6, which forms part of the substrate permeation pathway in the homologous Aquifex aeolicus leucine transporter. Expand
Probes for the cocaine receptor. Potentially irreversible ligands for the dopamine transporter.
Several potentially irreversible ligands (i.e., wash-resistant binding inhibitors) for the cocaine receptor site on the dopamine transporter, derived from (-)-cocaine or 3 beta-phenyltropan-2Expand